European journal of pharmacologyJan 30, 2026

Proton pump inhibitors may speed up blood vessel hardening by blocking cell cleanup in chronic kidney disease

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Feb 5, 2026

Abstract

An adjusted odds ratio of 5.365 indicates a significant link between proton pump inhibitor use and elevated coronary artery calcium scores in chronic kidney disease patients.

Proton pump inhibitors may increase cardiovascular risks, particularly vascular calcification, in patients with chronic kidney disease.
In CKD rat models, omeprazole treatment led to a dose-dependent increase in aortic calcification.
The treatment caused vascular smooth muscle cells to change from a contractile state to an osteoblastic state, indicating a shift towards calcification.
Mitochondrial dysfunction and impaired mitophagy were observed, linked to reduced levels of specific proteins involved in mitochondrial health.
Cyclooxygenase-2 was identified as a key mediator in this process, with omeprazole significantly increasing its expression.
Silencing COX-2 reversed the inhibition of mitophagy and the calcification of vascular smooth muscle cells induced by omeprazole.

Simplified

Prolonged use of proton pump inhibitors (PPIs) is associated with increased cardiovascular risks, including vascular calcification (VC). Patients with chronic kidney disease (CKD) are particularly vulnerable to the adverse vascular effects of PPIs. However, the underlying mechanism remains poorly understood. Clinical data from CKD patients treated with PPIs showed a higher incidence of elevated coronary artery calcium scores (adjusted odds ratio = 5.365, 95 % CI: 2.539-11.338, P < 0.001), indicating a link between PPI use and accelerated vascular damage. In CKD rats, omeprazole treatment dose-dependently induced aortic calcification, accompanied by a phenotypic switch of vascular smooth muscle cells (VSMCs) from a contractile to an osteoblastic state. This pathological process was associated with mitochondrial dysfunction and inhibited PINK1/Parkin-mediated mitophagy, as evidenced by reduced TOMM20, LC3B-II, PINK1, and Parkin protein levels, impaired mitochondrial-lysosomal colocalization (MitoTracker Green/LysoTracker Red staining), and swollen mitochondria with fewer mitophagosomes (transmission electron microscopy). Enhancement of mitophagy by rapamycin effectively mitigated omeprazole-induced VC. RNA sequencing identified cyclooxygenase-2 (COX-2) as a key mediator, with omeprazole significantly upregulating its expression. Silencing COX-2 reversed omeprazole-induced mitophagy inhibition and VSMC calcification. Esomeprazole and lansoprazole recapitulated these pro-calcific effects, indicating a class effect. Collectively, PPIs promote VC in CKD by upregulating COX-2, which directly inhibits PINK1/Parkin-related mitophagy. This study provides a novel COX-2-mitophagy axis in PPI-accelerated vascular injury, highlighting a potential therapeutic target for high-risk patients.

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Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

Proton pump inhibitors may speed up blood vessel hardening by blocking cell cleanup in chronic kidney disease

Abstract

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